The 22q11 Chromosomal Microdeletion Syndrome (22q11DS) is the most common survivable deletion syndrome known. In addition to heart, face and limb malformations, 22q11DS is defined by behavioral anomalies and increased susceptibility to several psychiatric diseases including schizophrenia. Apparently, 22q11 haploinsufficiency alters brain development or function, particularly forebrain regions and circuits compromised in behavioral and psychiatric disorders. Nevertheless, the effects of haploinsufficiency on expression or activity of 22q11 genes in the forebrain remain unknown. Our preliminary evidence suggests that 18 of 29 routine 22q11 homologues are expressed throughout the forebrain from early development through adulthood. Accordingly, we will evaluate the hypothesis that there is concerted expression of multiple 22q11 genes in specific cell classes distributed broadly in all forebrain subdivisions. If this is the case, multigenic haploinsufficiency at 22q11, rather than the function of any single gene, might establish a threshold for altered development of specific cell classes or circuits throughout the forebrain. This primary effect may be further amplified by alterations in mesenchymal/epithelial induction that mediates initial differentiation in the forebrain as well as the heart, limbs and face. Moreover, continued expression of 22q11 homologues, perhaps in specific differentiated cell classes, suggests that haploinsufficiency might further compromise function or maintenance of mature forebrain cells and circuit elements. To test our hypothesis we will determine cell-class specificity of a subset of the 22q11 homologues. We selected these genes based upon their significant and sustained expression levels in the developing and adult forebrain, genomic organization, inferred neural function and association with behavioral or psychiatric disorders. In addition, we will analyze the role of mesenchymal/epithelial interactions in modulating 22q11 gene expression. Finally, we will evaluate the consequences of 22q11 haploinsufficiency for expression patterns, levels and cellular phenotype in the developing and adult forebraIn. Thus, our experiments will establish the cellular substrates for the behavioral and psychiatric phenotypes seen in 22q11DS, and give insight into the developmental and genomic mechanisms by which haploinsufficiency at 22q11 compromises forebrain structure and function.